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- Department of Medicinal Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria (1)
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Das kolorektale Karzinom zählt zu den häufigsten Tumoren in den westlichen Nationen. Für die Heilung ist neben der frühen Diagnose und der korrekten Klassifikation in UICC-Stadien, die Auswahl einer effektiven individuellen Therapiestrategie von Bedeutung. Der Schlüssel für die erfolgreiche Verbesserung dieser und weiterer Schritte in der Behandlung eines kolorektalen Karzinom ist die Analyse der Interaktion zwischen kolorektalen Karzinomzellen und Immunzellen in einem 3D-Zellkulturmodell, das es ermöglicht, die in vivo Situation möglichst realitätsnah zu imitieren.
Im Vergleich zwischen einem 2D- und 3D-Zellkulturmodell konnten in dieser Arbeit bedeutende und reproduzierbare Unterschiede sowohl im Wachstumsverhalten und in der Zellmorphologie von Kolonkarzinomzellen (SW480-Zellen), Fibroblasten und Immunzellen (PBMC) als auch in deren Interaktion untereinander aufgezeigt werden.
PBMC induzieren im 2D-System sowohl bei der MK der SW480-Zellen als auch bei der KK mit Fibroblasten im Vergleich zum 3D-System deutlich mehr Apoptose. So gibt es bei der MK mit 1, 2 und 3 Millionen PBMC eine durchschnittliche Apoptosezunahme von 88 % nach 24 h und von 95 % nach 48 h. Bei der KK mit ebenfalls 1, 2 und 3 Millionen PBMC gibt es mit durchschnittlich 89 % nach 24 h und 92 % nach 48 h vergleichbare Apoptosezunahmen.
Zellkulturen auf azellularisierter Darmmatrix bieten den Raum für die bereits erwähnten wichtigen 3D-Zell-ECM- und Zell-Zellinteraktionen, realitätsnahe extrazelluläre Matrizen und soluble Substanzen, die eine sehr große Bedeutung für die Ausbildung tumorspezifischer Charakteristika haben wie z. B. Karzinogenese, Gewebsdifferenzierung Proliferationsgeschwindigkeit, Metastasierungspotential, Malignität, Angiogeneseeigenschaften und Mikroumgebungsbedingungen wie sie im System Mensch vorkommen.
Sie besitzen durch ihre viel komplexere histologische Struktur im Vergleich zu den zweidimensionalen Monolayer-Systemen eine höhere Aussagekraft, bieten eine bessere Vergleichbarkeit mit Tumorsystemen in lebenden Organismen und mindern die experimentelle Fehlinterpretationsraten im Vergleich zu 2D-Modellen. So ist es auch nicht verwunderlich, dass die Ergebnisse bezüglich der Apoptoserate der SW480-Zellen in beiden Zellkulturmodellen so unterschiedlich ausfallen. Durch eine gute strategische Planung der Durchführung weiterer Experimente und der Quantifizierung von weiteren möglichen Zytokinen könnte der Pool an möglichen Wegen hin zur Apoptose der SW480-Zelle eingeengt werden.
Unsere Ergebnisse zeigen, wie wichtig es ist, auch zukünftig weiter an dieser Thematik zu forschen, um so die Therapie des kolorektalen Karzinoms entscheidend zu verbessern. So wäre es durchaus vorstellbar, innerhalb dieses 3D-Modells durch Experimente, die beispielsweise die Tumorzellumgebung oder die Immunzelleigenschaften verändern, dem tumorzellbiologischen Verhalten und der immunologischen Tumor-Wirtsbeziehung in vivo entscheidend näher zu kommen.
(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III).
Das Medulloblastom ist der häufigste, maligne Hirntumor des Kindesalters. In den letzten Jahren ist es gelungen, molekularbiologisch definierte Subgruppen innerhalb dieser Tumorentität zu definieren, die sich durch ein unterschiedliches therapeutisches Ansprechen differenzieren lassen. Es werden vier Gruppen abgegrenzt: Tumore mit Aktivierung des WNT-Signalwegs, des SHH-Signalwegs, sowie der Gruppe 3, die sich vor allem durch eine Myc Amplifikation auszeichnen und Gruppe 4, in der MycN amplifiziert wird. Während Patienten mit SHH- und WNT-Tumoren eher eine günstige Prognose haben, ist der Bedarf an neuen Therapieansätzen für Patienten mit Gruppe 3- und Gruppe 4-Tumoren auf Grund der schlechten Prognose sehr hoch. Die aus einem malignen Pleuraerguss eines Gruppe 3-Medulloblastom Patienten gewonnenen Tumorzellen konnten erfolgreich als permanente Zelllinie etabliert sowie in vitro und in vivo charakterisiert werden. Dieses Tumormodell habe ich in meiner Dissertationsarbeit genutzt um die zytotoxische Wirkung neuer Zytostatika und Inhibitoren Kombinationen auf das Gruppe 3-Medulloblastom in vitro und im Tiermodell zu untersuchen. Bei der Auswahl neuer Therapieansätze galt die Maßgabe, Substanzen zu wählen, die für den klinischen Einsatz geeignet sind, neue gezielte zytostatische Mechanismen aufweisen und bei denen bereits publizierte Vorarbeiten nahelegen, dass diese das ZNS tatsächlich erreichen. In unserem in vitro Modell testeten wir 23 Substanzen und wählten dann die fünf vielversprechendsten für das subkutane Tumormausmodell aus. Als Vergleichsgruppen für das Therapieansprechen wählten wir die Kombination aus Cisplatin und Etoposid, die gerade bei den Patienten mit einem HochrisikoMedulloblastom die Therapie der Wahl ist. Im ersten Tierversuch konnte gezeigt werden, dass Gemcitabin als Monotherapie den gleichen zytotoxischen Therapieeffekt zeigt, wie Cisplatin und Etoposid in Kombination. Deshalb war nun das Ziel eine Substanz zu finden, welche dann in Kombination mit Gemcitabin einen besseres Therapieansprechen als die Standardtherapie zeigt. Bei der Tumorpräparation im initialen Tierversuch fiel auf, dass die Tumoren stark vaskularisiert sind. Nach dieser Beobachtung stellten wir uns die Fragen, ob die Inhibition des Vaskularisierungsvorgangs im Tumor einen additiven zytotoxischen Effekt auf das Tumorwachstum hat. Daraufhin erweiterten wir die Suche nach geeigneten Substanzen für das Gruppe 3-Medulloblastom um Multikinaseinhibitoren, die auch VEGF-Rezeptoren inhibieren. Überraschenderweise konnten wir zeigen das Gemcitabin in Kombination mit verschiedenen VEGF-Rezeptor-Inhibitoren in den Toxizitätsversuchen in vitro eine 10.000 fach niedrigere EC50 hat als die Kombination aus Cisplatin und Etoposid. Auch in den anschließenden Tierversuchen konnten wir zeigen, dass Gemcitabin in Kombination mit Axitinib einen besseren Therapieerfolg bezogen auf das Tumorwachstum zeigt, als die bisherige Standardtherapie. Darüber hinaus verloren die Tiere, die mit Gemcitabin und Axitinib behandelt wurden deutlich weniger an Gewicht, als die Tiere die die Standardtherapie erhielten. Zusammenfassend können wir zeigen, dass Axitinib, ein neuer pan-VEGF-Rezeptor-Inhibitor der bisher nur in anderen Tumorentitäten wie dem Nierenzellkarzinom zum Einsatz kommt, in Kombination mit Gemcitabin, einem Nukleosidanalogon, einen deutlichen zytotoxischen Effekt an Medulloblastom Zelllinien in vitro als auch im subkutanen und orthotopen Tiermodell hat. Diese Ergebnisse könnten die Basis sein für neue therapeutische Strategien gegen das Gruppe 3-Medulloblastom bei Kindern, die die bisherige Therapie nicht mehr tolerieren oder bereits irreversible Nebenwirkungen der Standardtherapie entwickelt haben
(1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. Median maternal age was 33 (IQR, 30–36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28–35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome.
This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1–1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42–0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.
The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.
(1) Background: We aimed to evaluate the effect of proposed “microbiome-stabilising interventions”, i.e., breastfeeding for ≥3 months and prophylactic use of Lactobacillus acidophilus/ Bifidobacterium infantis probiotics on neurocognitive and behavioral outcomes of very-low-birthweight (VLBW) children aged 5–6 years. (2) Methods: We performed a 5-year-follow-up assessment including a strength and difficulties questionnaire (SDQ) and an intelligence quotient (IQ) assessment using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III test in preterm children previously enrolled in the German Neonatal Network (GNN). The analysis was restricted to children exposed to antenatal corticosteroids and postnatal antibiotics. (3) Results: 2467 primary school-aged children fulfilled the inclusion criteria. In multivariable linear regression models breastfeeding ≥3 months was associated with lower conduct disorders (B (95% confidence intervals (CI)): −0.25 (−0.47 to −0.03)) and inattention/hyperactivity (−0.46 (−0.81 to −0.10)) as measured by SDQ. Probiotic treatment during the neonatal period had no effect on SDQ scores or intelligence. (4) Conclusions: Prolonged breastfeeding of highly vulnerable infants may promote their mental health later in childhood, particularly by reducing risk for inattention/hyperactivity and conduct disorders. Future studies need to disentangle the underlying mechanisms during a critical time frame of development.
Data on biomarker-assisted diagnosis of invasive aspergillosis (IA) in pediatric patients is scarce. Therefore, we conducted a cohort study over two years including 404 serum specimens of 26 pediatric patients after allogeneic hematopoietic stem cell transplantation (alloSCT). Sera were tested prospectively twice weekly for Aspergillus-specific DNA, galactomannan (GM), and retrospectively for (1→3)-β-D-glucan (BDG). Three probable IA and two possible invasive fungal disease (IFD) cases were identified using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC) 2019 consensus definitions. Sensitivity and specificity for diagnosis of probable IA and possible IFD was 80% (95% confidential interval (CI): 28–99%) and 55% (95% CI: 32–77%) for BDG, 40% (95% CI: 5–85%) and 100% (95% CI: 83–100%) for GM, and 60% (95% CI: 15–95%) and 95% (95% CI: 75–100%) for Aspergillus-specific real-time PCR. However, sensitivities have to be interpreted with great caution due to the limited number of IA cases. Interestingly, the low specificity of BDG was largely caused by false-positive BDG results that clustered around the date of alloSCT. The following strategies were able to increase BDG specificity: two consecutive positive BDG tests for diagnosis (specificity 80% (95% CI: 56–94%)); using an optimized cutoff value of 306 pg/mL (specificity 90% (95% CI: 68–99%)) and testing BDG only after the acute posttransplant phase. In summary, BDG can help to diagnose IA in pediatric alloSCT recipients. However, due to the poor specificity either an increased cutoff value should be utilized or BDG results should be confirmed by an alternative Aspergillus assay.
Pediatric tumors-mediated inhibitory effect on NK cells: the case of neuroblastoma and Wilms' tumors
(2021)
Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms’ tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.
Wilms' tumor primary cells display potent immunoregulatory properties on NK cells and macrophages
(2021)
The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56\(^+\)/CD133\(^−\)) or an epithelial (CD56\(^−\)/CD133\(^+\)) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.